EXPRESS: Ascorbic acid relieves neuropathic pain and depressive behavior by reducing inflammation and activating antioxidant responses.

Neuropathic pain (NP), a specific subtypes of chronic pain, can induce depression-like behavior, presenting significant challenges for clinical treatment. Ascorbic acid (AA) is a free radical scavenger; however, its regulatory effects on NP, particularly within the spinal cord, remain ambiguous. In this research, we examined the impact of AA on NP and associated depression-like behavior by establishing a spinal nerve injury (SNI) NP model. Behavioral tests showed that mice in the SNI group exhibited hyperalgesia and depression-like behavior. Contrasted with the control group, the SNI group showed attenuated antioxidant responses (impaired Nrf2 signaling), excessive NLRP3 inflammasome activation, and elevated AMPK activity in spinal cord tissues. However, treatment with AA alleviated NP and depression-like behavior in mice with SNI by suppressing NLRP3-mediated inflammation and enhancing Nrf2-driven antioxidant responses. In vivo electrophysiology demonstrated that AA reversed the increase in theta, alpha, and beta band energies in mice with SNI. The results suggest that AA mitigates NP and comorbid depression-like behavior by inhibiting the activity of NLRP3 inflammasome and activating the Nrf2 pathway. Its ability to normalize neurophysiological rhythms further supports its therapeutic potential for NP. These findings imply that AA is a novel therapeutic agent for NP.